1,4-diazocane compound or salt thereof

ABSTRACT

A method may produce an isoquinoline-6-sulfonamide derivative useful as a medicinal drug; and an intermediate which is used for the method, and more specifically, a 1,4-diazocane compound of formula (8), wherein R 4  is an amino protecting group, or a salt thereof.

FIELD OF THE INVENTION

The present invention relates to a 1,4-diazocane compound useful as asynthetic intermediate for medicinal drugs, and use thereof.

BACKGROUND OF THE INVENTION

Compounds in which a nitrogen-containing saturated heterocyclic ringsuch as diazocane binds to an isoquinoline ring at the 6-positionthrough a sulfonyl group are known to have a potent ocular hypotensiveaction and be useful as therapeutic drugs for ocular hypertension suchas glaucoma (Patent Literature 1). Of these isoquinoline-6-sulfonamidederivatives, (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline offormula (I):

or a salt thereof is known to have a particularly excellent ocularhypotensive action and be useful as a therapeutic drug for glaucoma orocular hypertension. Patent Literature 1 indicates that the compound canbe produced in accordance with the following reaction formula.

CITATION LIST Patent Literature

Patent Literature 1: JP-B-4915010

SUMMARY OF THE INVENTION Technical Problem

However, the method for producing a compound (I) according to PatentLiterature 1 has the problem that the yields in reaction ofisoquinoline-6-sulfonyl chloride with a diamine compound and subsequent1,4-diazocane-forming reaction are low, resulting in increasedproduction cost, and a step of purification by column chromatography isnecessary. Thus, the method is not satisfactory as an industrial methodfor producing a medicinal drug product.

Accordingly, an object of the present invention is to provide a novelmethod for producing a compound of formula (I) via a novel intermediate.

Solution to Problem

Thus, the present inventors conducted studies for developing a novelmethod for producing a compound of formula (I), and resultantlysuccessfully synthesized a novel 1,4-diazocane compound having an aminoprotecting group, and found that use of the compound enables productionof a compound of formula (I) in high yield. In this way, the presentinvention was completed.

That is, the present invention relates to the following aspects [1] to[5].

[1] A 1,4-diazocane compound of formula (A):

or a salt thereof, wherein R^(2a) represents a hydrogen atom or an aminoprotecting group and R⁴ represents an amino protecting group.

[2] A compound of formula (B):

a salt thereof or a hydrate thereof,wherein R² represents an amino protecting group, R⁴ represents ahydrogen atom or an amino protecting group and Z represents a number offrom 0 to 1.

[3] A method for producing an isoquinoline-6-sulfonamide derivative offormula (11):

or a salt thereof, the method comprising reacting a 1,4-diazocanecompound of formula (8):

or a salt thereof, wherein R⁴ represents an amino protecting group,with a quinoline-6-sulfonyl halide of formula (9):

or a salt thereof, wherein X² represents a halogen atom, and thencarrying out an elimination reaction of amino protecting group.

[4] A method for producing a 1,4-diazocane compound of formula (A):

or a salt thereof, wherein R^(2a) represents a hydrogen atom or an aminoprotecting group and R⁴ represents an amino protecting group, the methodcomprising reacting a compound of formula (6):

wherein R² and R⁴ each represent an amino protecting group,with an azodicarboxylic acid ester and triphenylphosphine, and thencarrying out an elimination reaction of amino protecting group ifnecessary.

[5] A method for producing a compound of formula (B):

wherein R² represents an amino protecting group, R⁴ represents ahydrogen atom or an amino protecting group and Z represents a number offrom 0 to 1,, a salt thereof or a hydrate thereof, the method comprising reacting acompound of formula (3):

wherein R² represents an amino protecting group and R³ represents ahalogen atom or a substituted sulfonyloxy group,with 4-amino-1-butanol, and then protecting the amino group ifnecessary.

Advantageous Effect of the Invention

According to the present invention, a compound of formula (A) or a saltthereof can be produced in high yield from inexpensive raw materials.

DETAILED DESCRIPTION OF THE INVENTION

A 1,4-diazocane compound of formula (A) or a salt thereof is useful asan intermediate for production of an isoquinoline-6-sulfonamidederivative of formula (11) or a salt thereof.

In formula (A), R^(2a) represents a hydrogen atom or an amino protectinggroup. The amino protecting group of R^(2a) may be a protecting groupcapable of being eliminated under conditions different from those forthe amino protecting group of R⁴, and is preferably anitrobenzenesulfonyl group which acts also as an amino group activatinggroup, from the viewpoint of forming a 1,4-diazocane ring by Mitsunobureaction of aminoalcohol. Here, examples of the nitrobenzenesulfonylgroup include 2-nitrobenzenesulfonyl group (Ns), 4-nitrobenzenesulfonylgroup (Nos) and 2,4-dinitrobenzenesulfonyl group (DNs). R^(2a) is morepreferably a hydrogen atom.

Examples of the amino protecting group of R⁴ include carbamate-basedprotecting groups such as t-butoxycarbonyl group (Boc),benzyloxycarbonyl group (Cbz), 9-fluorenylmethylcarbonyl group (Fmoc),2,2,2-trichloroethoxycarbonyl group (Troc) and allyloxycarbonyl group;amide-based protecting groups such as trifluoroacetyl group; phthaloylgroup; and p-toluenesulfonyl group. From the viewpoint of ease ofdeprotection, carbamate-based protecting groups are preferable, and thet-butoxycarbonyl group (Boc) is more preferable.

Of compounds of formula (A), steric isomers of formula (A1) areparticularly preferable.

wherein R^(2a) and R⁴ are the same as described above.

Here, Rea is more preferably a hydrogen atom.

A compound of formula (B), a salt thereof or a hydrate thereof is usefulas an intermediate for production of a compound of formula (A) or a saltthereof.

In formula (B), R² represents an amino protecting group. The aminoprotecting group of R² may be a protecting group capable of beingeliminated under conditions different from those for the aminoprotecting group of R⁴, and is preferably nitrobenzenesulfonyl groupwhich acts also as an amino group activating group, from the viewpointof forming a 1,4-diazocane ring by Mitsunobu reaction of aminoalcohol.Here, examples of the nitrobenzenesulfonyl group include2-nitrobenzenesulfonyl group (Ns), 4-nitrobenzenesulfonyl group (Nos)and 2,4-dinitrobenzenesulfonyl group (DNs). R⁴ represents a hydrogenatom or an amino protecting group, and is preferably the same asdescribed above. Z is preferably a number of from 0 to 1.

Of compounds of formula (B), steric isomers of formula (B1):

wherein R², R⁴ and Z are the same as described above, are particularlypreferable.

The production method in the present invention can be represented by thefollowing reaction formulae which show the reactions beginning with astarting material.

wherein R¹ and R⁵ each independently represent a hydrogen atom, ahalogen atom, a cyano group, an alkyl group, a halogenoalkyl group, analkenyl group, an alkoxy group, an alkylthio group, a hydroxy group, amercapto group, a nitro group, an aryl group, an amino group or anaminoalkylthio group, R² represents an amino protecting group, R³represents a substituted sulfonyloxy group or a halogen atom, L¹represents a halogen atom, a hydroxy group or a leaving group, Y¹represents a halogen atom or a sulfinyl group, R⁴ represents an aminoprotecting group, and Z represents a number of from 0 to 1.

Each reaction step will be described below.

(1) Step of producing compound (9)

Compound (9) can be produced using commercially available6-aminoisoquinoline (13) or 6-bromoisoquinoline (12). For synthesis ofcompound (9) from compound (12), a known method can be used.

(2) Step of producing compound (2) from compound (1)

Preferably, (R)-2-amino-1-propanol is used as compound (1). The reagentused for protecting the amino of compound (1) is preferably anitrobenzenesulfonyl halide such as nitrobenzenesulfonyl chloride asdescribed above.

Preferably, this reaction is carried out in the presence of an aromaticamine such as pyridine, or a tertiary amine such as triethylamine,dimethylaniline or diisopropylethylamine. The amount of the amine usedis preferably from 1 to 5 times, more preferably from 1 to 3 times amole of compound (1). Preferably, an ether-based solvent such astetrahydrofuran, diethyl ether, dioxane or cyclopentylmethyl ether, apolar solvent such as acetonitrile, or an aromatic hydrocarbon-basedsolvent such as toluene is used as a reaction solvent. The reaction maybe carried out at from −10° C. to 50° C. for from 1 hour to 12 hours.

(3) Step of producing compound (3) from compound (2)

Examples of R³—Y¹ which is reacted with compound (2) include substitutedsulfonyl halides and thionyl halides. Examples of the substitutedsulfonyl halides include alkanesulfonyl halides such as methanesulfonylhalides, and arylsulfonyl halides such as p-toluenesulfonyl halides.Examples of the thionyl halides include thionyl chloride and thionylbromide.

Preferably, the reaction of compound (2) with substituted sulfonylhalide is carried out in the presence of, for example, an aromatic aminesuch as pyridine or a tertiary amine such as triethylamine ordimethylaniline. The amount of the amine used is preferably from 1 to 5times, more preferably from 1 to 3 times a mole of compound (2).Preferably, an ether-based solvent such as tetrahydrofuran, diethylether or dioxane, a polar solvent such as acetonitrile, or an aromatichydrocarbon-based solvent such as toluene is used as a solvent for thereaction. The reaction may be carried out at from 0° C. to 100° C. forfrom 1 hour to 12 hours.

Preferably, the reaction of compound (2) with a thionyl halide such asthionyl chloride is carried out at from 60 to 80° C. for from 3 to 24hours in the presence of an aromatic hydrocarbon-based solvent such astoluene or xylene, or an aromatic amine such as pyridine.

(4) Step of producing compound (5) from compound (3)

Compound (5) can be produced by reacting compound (3) with4-amino-1-butanol (4). Preferably, the reaction is carried out in thepresent of a base. As the base, an alkali metal carbonate such aspotassium carbonate or sodium carbonate, or an alkali metal hydroxidesuch as potassium hydroxide or sodium hydroxide can be used. The amountof the base used is preferably from 1 to 10 times, more preferably from1 to 5 times a mole of compound (3). Preferably, a polar solvent such asacetonitrile is used as a reaction solvent. The reaction may be carriedout at from 10° C. to 150° C. for from 1 hour to 12 hours. Compound (5)can be isolated in a hydrate form.

(5) Step of producing compound (6) from compound (5)

Compound (6) can be obtained by protecting the amino group of compound(5). As a compound used for protecting the amino group of compound (5),a compound corresponding to the amino protecting group of R⁴ is used.For example, when the amino group is protected with a t-butoxycarbonylgroup, di-t-butyl dicarbonate is used. Preferably, reaction forintroduction of the protecting group is carried out in the presence ofan aromatic amine such as pyridine, or a tertiary amine such astriethylamine or dimethylaniline. The amount of the amine used ispreferably from 1 to 10 times, more preferably from 1 to 3 times a moleof compound (5). As a reaction solvent, halogenated hydrocarbon-basedsolvents such as dichloromethane, alcohol-based solvents such asmethanol, ether-based solvents such as tetrahydrofuran and diethylether, nitrile-based solvents such as acetonitrile, water and the like,or a mixture of any of these solvents at an appropriate ration is used.The reaction may be carried out at from 0° C. to 150° C. for from 1 hourto 12 hours.

(6) Step of producing compound (7) from compound (6)

Preferably, Mitsunobu reaction is utilized for the method for producingcompound (7) by cyclizing compound (6). That is, compound (7) isobtained by reacting compound (6) with an azodicarboxylic acid ester andtriphenyl phosphine.

Examples of the azodicarboxylic acid ester include azodicarboxylic acidalkyl esters such as diisopropyl azodicarboxylate and diethylazodicarboxylate. The amount of the azodicarboxylic acid ester used ispreferably from 1 to 5 times, more preferably from 1 to 3 times a moleof compound (6). The amount of triphenylphosphine used is preferablyfrom 1 to 5 times, more preferably from 1 to 3 times a mole of compound(6). The reaction may be carried out at from 0 to 100° C. for from 1 to12 hours in an ether-based solvent such as tetrahydrofuran or anaromatic hydrocarbon-based solvent such as toluene.

(7) Step of producing compound (8) from compound (7)

Compound (8) can be obtained by eliminating the amino protecting groupR² of compound (7).

Elimination means such as a base or reduction can be selected accordingto the type of the amino protecting group of R². For example, when R² isa nitrobenzenesulfonyl group, deprotection can be performed under mildconditions by reaction of a thiol such as thiophenol or dodecanthiol. Analkanethiol with a long-chain alkyl such as dodecanthiol is preferablebecause it is less odorous. The amount of the thiol used is preferablyfrom 1 to 5 times, more preferably from 1 to 3 times a mole of compound(7). Preferably, deprotection reaction is carried out in the presence ofa base such as potassium carbonate, sodium carbonate, lithium hydroxideor a hydrate thereof. The amount of the base used is preferably from 1to 20 times, more preferably from 1 to 10 times a mole of compound (7).The reaction may be carried out at room temperature to 100° C. for from30 minutes to 5 hours in a solvent such as a polar solvent such asacetonitrile or dimethylformamide, or an aromatic hydrocarbon-basedsolvent such as toluene.

(8) Step of producing compound (10) by reacting compound (8) withcompound (9)

Compound (10) can be obtained by reacting compound (8) with anisoquinoline-6-sulfonyl halide or an acid addition salt thereof (9).Preferably, the reaction is carried out in the presence of an aromaticamine such as pyridine, or an amine such as triethylamine,dimethylaniline or dimethylaminopyridine. The amount of the tertiaryamine used is preferably from 1 to 5 times, more preferably from 1 to 3times a mole of compound (8). The reaction can be carried out in a polarsolvent such as acetonitrile or dimethylformamide, or an aromatichydrocarbon-based solvent such as toluene. As reaction conditions, thereaction may be carried out at from 0 to 100° C. for from 1 to 5 hours.

(9) Step of producing compound (11) from compound (10)

Compound (11) can be obtained by eliminating the amino protecting group(R⁴) of compound (10). For deprotection reaction of R⁴, means such as abase, an acid or reduction can be selected according to the type of R⁴.For example, when R⁴ is a t-butoxycarbonyl group, deprotection may beperformed under acidic conditions. For establishing acidic conditions, amineral acid such as hydrochloric acid or sulfuric acid, or a strongacid such as trifluoroacetic acid can be used. For deprotection of thebenzyloxycarbonyl group, hydrogenation reaction using a palladiumcatalyst, Birch reduction or the like can be employed. The deprotectionreaction may be carried out at from 0 to 150° C. for from 1 hour to 20hours in, for example, an ether-based solvent such as dioxane, anaromatic hydrocarbon-based solvent such as toluene, or an ester-basedsolvent such as ethyl acetate.

Preferably, compound (11) is isolated as an acid addition salt such as ahydrochloride or a sulfate. Particularly preferably, compound (11) isisolated as a hydrochloride from the viewpoint of use as a medicinaldrug product. For isolating compound (11) as an acid addition salt, itis preferable that in an organic solvent, an acid such as hydrochloricacid be added to form an acid addition salt. For example, when compound(11) is isolated as a hydrochloride, a hydrochloride of compound (11)can be obtained efficiently.

According to the method of the present invention, compound (11) or anacid addition salt thereof, which is useful as a medicinal drug, can beindustrially advantageously obtained.

EXAMPLES

The present invention will now be described in more detail by way ofExamples.

Example 1

(1) Steps 1 and 2

(R)-2-amino-1-propanol (3.82 g) was dissolved in THF (150 mL),triethylamine (7.08 mL) and 2-nitrobenzenesulfonyl chloride (11.2 g)were added at 0° C., and the mixture was stirred at room temperature for2 hours. Disappearance of the raw material was confirmed by TLC,distilled water was then added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated saline, and driedwith anhydrous sodium sulfate. Filtration was performed, and thefiltrate was concentrated under reduced pressure to obtain(R)—N-(2-hydroxy-1-methylethyl)-2-nitrobenzenesulfonamide in the form ofa white solid (13.4 g). To this was added THF (150 mL) to dissolve thewhite solid, triethylamine (7.08 mL) and methanesulfonyl chloride (3.93mL) were then added at 0° C., and the mixture was stirred at roomtemperature for 2 hours. Disappearance of the raw material was confirmedby TLC, distilled water was then added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,and dried with anhydrous sodium sulfate. Filtration was performed, andthe filtrate was concentrated under reduced pressure. The obtained solidwas washed with n-hexane/ethyl acetate=8/1 to obtain(R)—N-(1-methanesulfonyloxypropan-2-yl)-2-nitrobenzenesulfonamide in theform of a white solid (14.9 g, yield: 86%).

2;¹H NMR (500 MHz, CDCl₃, δ ppm): 1.34 (d, J=6.5 Hz, 3H), 2.64 (d, J=7Hz, 1H), 3.49-3.52 (m, 1H), 3.57-3.64 (m, 2H), 7.72-7.77 (m, 2H),7.86-7.89 (m, 1H), 8.16-8.19 (m, 1H). ESI-MS m/z: 261 [M+H]⁺, 283[M+Na]⁺, 543 [2M+Na]⁺.3;¹H NMR (500 MHz, CDCl₃, δ ppm): 1.24 (d, J=7.0 Hz, 3H), 2.99 (s, 3H),3.87-3.91 (m, 1H), 4.11-4.18 (m, 2H), 5.52 (d, J=8 Hz, 1H), 7.75-7.79(m, 2H), 7.90-7.92 (m, 1H), 8.16-8.17 (m, 1H). ESI-MS m/z: 339 [M+H]⁺,361 [M+Na]′, 699 [2M+Na]′.

(2) Steps 3 and 4

4-amino-1-butanol (636 mg) and potassium carbonate (2.45 g) weresuspended in acetonitrile (8 mL), and the suspension was stirred at 70°C. To this was added dropwise(R)—N-(1-methanesulfonyloxypropan-2-yl)-2-nitrobenzenesulfonamide (2.00g) dissolved in acetonitrile (30 mL) for 60 minutes. The reaction liquidwas further stirred at this temperature for 2 hours, disappearance ofthe raw material was then confirmed by TLC, and the reaction liquid wascooled to room temperature. Water was added to the reaction liquid, andthe mixture was extracted with ethyl acetate. The organic layer wasdried with anhydrous sodium sulfate, and filtered. Subsequently, thefiltrate was concentrated under reduced pressure to obtain(R)—N-[2-(4-hydroxy-butylamino)-1-methylethyl]-2-nitrobenzenesulfonamideas a crude product (2.14 g). To this was added dichloromethane (40 mL),and the mixture was cooled to 0° C. To this were added triethylamine(0.822 mL) and di-tert-butyl dicarbonate (1.28 g), and the mixture wasstirred at room temperature for 2 hours. Disappearance of the rawmaterial was confirmed by TLC, 1 N hydrochloric acid cooled to 0° C. wasthen added, and the organic layer was washed. Subsequently, the organiclayer was washed with a saturated sodium hydrogencarbonate solution,dried with anhydrous sodium sulfate, and filtered. Subsequently, thefiltrate was concentrated under reduced pressure to obtain(R)-tert-butyl4-hydroxybutyl-2-(2-nitrophenylsulfonamide)propylcarbamate (2.33 g,yield: 91%).

4;¹H NMR (500 MHz, CDCl₃, δ ppm): 1.11 (d, J=7.0 Hz, 3H), 1.52-1.55 (m,2H), 1.58-1.63 (m, 2H), 2.55-2.68 (m, 4H), 3.56-3.61 (m, 3H), 7.72-7.76(m, 2H), 7.85-7.87 (m, 1H), 8.16-8.18 (m, 1H). ESI-MS m/z: 332 [M+H]⁺,354 [M+Na]⁺, 685 [2M+Na]⁺.5;¹H NMR (500 MHz, CDCl₃, δ ppm): 1.08 (brs, 3H), 1.42-1.57 (m, 13H),3.05-3.42 (m, 4H), 3.63-3.64 (m, 2H), 3.83 (brs, 1H), 7.72 (brs, 2H),7.84 (brs, 1H), 8.11 (d, J=7.0 Hz, 1H). ESI-MS m/z: 332[M-CO₂C(CH₃)₃+H]+, 432 [M+H]⁺, 454 [M+Na]⁺, 885 [2M+Na]⁺.

(3) Step 5

(R)-tert-butyl4-hydroxybutyl-2-(2-nitrophenylsulfonamide)propylcarbamate (2.33 g) andtriphenylphosphine (2.12 g) were dissolved in tetrahydrofuran (20 mL)under the nitrogen flow, and diisopropyl azodicarboxylate (1.60 mL) wasadded dropwise at 0° C. The reaction liquid was stirred at roomtemperature for 2 hours, disappearance of the raw material was confirmedby TLC, and the reaction liquid was concentrated under reduced pressure.The obtained residue was washed with hexane, followed by adding ether.The precipitate was removed, and the filtrate was concentrated to obtain(R)-tert-butyl3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate as anorange-colored oily crude product (4.3 g).

6;¹H NMR (500 MHz, CDCl₃, δ ppm): 0.92, 0.98 (d, J=5.7 Hz, 3H), 1.48 (s,9H), 1.67-1.77 (m, 2H), 1.85-1.95 (m, 2H), 3.07-3.12 (m, 1H), 3.32-3.50(m, 4H), 3.69-3.71 (m, 1H), 4.16-4.20 (m, 1H), 7.57-7.59 (m, 1H),7.64-7.69 (m, 2H), 7.97, 8.02 (d, J=6.5 Hz, 1H). ESI-MS m/z: 414 [M+H]⁺,436 [M+Na]⁺, 849 [2M+Na]⁺.

(4) Step 6

(R)-tert-butyl3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate (4.3 g)was dissolved in acetonitrile (20 mL), and potassium carbonate (4.0 g)was added. To this was added thiophenol (1.2 mL) at room temperature,and the mixture was stirred at 50° C. for 1 hour. Disappearance of theraw material was confirmed by TLC, insoluble materials were thenfiltered, and the filtrate was concentrated under reduced pressure. 2 Nhydrochloric acid was added to the residue to a pH of 3. The mixture waswashed with ethyl acetate, and the aqueous layer was adjusted to a pH ofabout 9 with potassium carbonate, and extracted with ethyl acetate. Theorganic layer was dried with anhydrous sodium sulfate, and filtered.Subsequently, the filtrate was concentrated under reduced pressure toobtain (R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate in the formof a yellow oily material (758 mg, yield in two steps: 61%)

7;¹H NMR (500 MHz, CDCl₃, δ ppm): 1.04 (d, J=6.0 Hz, 3H), 1.46 (s, 9H),1.53-1.77 (m, 4H), 2.53-2.70 (m, 2H), 2.99-3.17 (m, 3H), 3.58-3.92 (m,2H). ESI-MS m/z: 229 [M+H]⁺.

(5) Step 7

(R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate (1.09 g) andtriethylamine (1.32 mL) were dissolved in acetonitrile (20 mL),6-chlorosulfonylisoquinoline hydrochloride (1.26 g) was added undercooling with iced water, and the mixture was stirred for 2 hours undercooling with iced water. Disappearance of the raw material was confirmedby TLC, the reaction product was then concentrated under reducedpressure, water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated saline, dried withanhydrous sodium sulfate, and then filtered. The filtrate wasconcentrated under reduced pressure to obtain (R)-tert-butyl4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate in theform of a yellow oily material (2.08 g).

8;¹H NMR (500 MHz, CDCl₃, δ ppm): 0.82, 0.90 (d, J=6.8 Hz, 3H), 1.48 (s,9H), 1.73-2.02 (m, 4H), 2.98-3.08 (m, 1H), 3.31-3.51 (m, 4H), 3.60-3.63(m, 1H), 4.22-4.26 (m, 1H), 7.77 (d, J=4.8 Hz, 1H), 7.91 (d, J=8.5 Hz,1H), 8.10 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 8.67 (d, J=4.8 Hz, 1H), 9.35(s, 1H). ESI-MS m/z: 420 [M+H]⁺, 839 [2M+H]⁺, 861 [2M+Na]⁺.

(7) Step 8

(R)-tert-butyl4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate (2.08g) was dissolved in ethyl acetate (8 mL), and a 4 M hydrochloricacid/1,4-dioxane solution (12 mL) was added at room temperature. Themixture was stirred at room temperature for 16 hours, and ethyl acetatewas then added to wash the solid. The solvent was removed with apipette, and the remaining solid was dissolved by adding water. Thisaqueous layer was washed once with ethyl acetate, and then made basic byadding sodium hydroxide. Thereafter, the aqueous layer was extractedwith dichloromethane, and dried with anhydrous sodium sulfate.Filtration was performed, and the filtrate was then concentrated underreduced pressure to obtain(R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline as a yellow oilymaterial (1.17 g, yield in two steps: 77%).

9;¹H NMR (500 MHz, CDCl₃, δ ppm): 0.8 (d, J=6.5 Hz, 3H), 1.50-1.65 (m,2H), 1.89-1.94 (m, 1H), 2.01-2.04 (m, 1H), 2.67-2.71 (m, 1H), 2.77-2.82(m, 1H), 2.95-3.00 (m, 2H), 3.48-3.59 (m, 2H), 3.97-4.00 (m, 1H), 7.76(d, J=6.0 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.37(s, 1H), 8.66 (d, J=6.0 Hz, 1H), 9.34 (s, 1H). ESI-MS m/z: 320 [M+H]′,639 [2M+H]′.

(8) Step 9

(R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline (0.69 g) wasdissolved in ethyl acetate (5 mL), 1 M hydrochloric acid/diethyl ether(2.0 mL) was added at room temperature, and the mixture was stirred for20 hours. The precipitate was washed with ethyl acetate andsimultaneously filtered to obtain(R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline hydrochloridein the form of a white solid (0.7 g, yield: 91%).

10;¹H NMR (400 MHz, D₂O, δ ppm): 0.73 (d, J=6.8 Hz, 3H), 1.82-2.20 (m,4H), 3.18-3.40 (m, 4H), 3.50-3.60 (m, 1H), 3.72-3.80 (m, 1H), 4.40-4.52(m, 1H), 7.95 (d, J=6.0 Hz, 1H), 8.0 (dd, J=1.8, 8.7 Hz, 1H), 8.28 (d,J=8.7 Hz, 1H), 8.51 (s, 1H), 8.57 (d, J=6.0 z, 1H), 9.31 (s, 1H). ESI-MSm/z: 320 [M+H]⁺, 639 [2M+H]⁺. Anal. calcd for C₁₆H₂₂ClN₃O₂S: C, 54.00%;H, 6.23%; N, 11.81%. Found: C, 53.90%; H, 6.23%; N, 11.60%.

Example 2

(1) Step 1

(R)-2-amino-1-propanol (20.0 g) was dissolved in tetrahydrofuran (800mL), and triethylamine (26.9 g) was added, and the mixture was cooled to0° C. 2-nitrobenzenesulfonyl chloride (59.0 g) was added, and themixture was stirred at 25° C. for 3 hours.

After completion of the reaction, water was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with saline,dried with sodium sulfate, and concentrated to obtain(R)—N-(2-hydroxy-1-methylethyl)-2-nitrobenzenesulfonamide (72.1 g).

The NMR spectral data was identical to that in Example 1.

(2) Step 2

(R)—N-(2-hydroxy-1-methylethyl)-2-nitrobenzenesulfonamide (17.3 g) wasdissolved in tetrahydrofuran (40 mL), thionyl chloride (27.7 g) wasadded, and the mixture was stirred at 60° C. for 5 hours.

After completion of the reaction, the reaction product was brought backto room temperature, toluene was added, and the mixture wasconcentrated. Toluene was added to the residue, and the precipitate wasfiltered to obtain(R)—N-(2-chloro-1-methylethyl)-2-nitrobenzenesulfonamide (10.4 g).

11;¹H NMR (300 MHz, CDCl₃, δ ppm): 1.26 (d, J=6.6 Hz, 3H), 3.55 (d,J=4.4 Hz, 2H), 3.84-3.96 (m, 1H), 5.61 (d, J=7.7 Hz, 1H), 7.74-7.80 (m,2H), 7.89-7.93 (m, 1H), 8.14-8.18 (m, 1H).

MS m/z: : 229 [M+H]⁺

Melting point: 90° C.IR: 3304, 3281, 1540, 1426, 1357, 1339, 1163, 748, 601, 562 (cm⁻¹)

(3) Step 3

4-amino-1-butanol (5.1 g) was dissolved in acetonitrile (40 mL),potassium carbonate (14.9 g) was added, and the mixture was heated to70° C. A solution of(R)—N-(2-chloro-1-methylethyl)-2-nitrobenzenesulfonamide (10.0 g) andacetonitrile (70 mL) was added dropwise. After the dropwise addition,the mixture was stirred at 70° C. for 2 hours.

After completion of the reaction, the reaction product was brought backto room temperature, water was added, and the mixture was extracted withacetonitrile. The organic layer was concentrated, ethyl acetate wasadded to the obtained residue, and the precipitated yellow solid wastaken by filtration to obtain(R)—N-[2-(4-hydroxy-butylamino)-1-methylethyl]-2-nitrobenzenesulfonamidemonohydrate (7.8 g).

12;¹H NMR (300 MHz, CDCl₃, δ ppm): 1.10 (d, J=7.0 Hz, 3H), 1.50-1.65 (m,4H), 2.55-2.70 (m, 4H), 3.55-3.64 (m, 3H), 7.72-7.79 (m, 2H), 7.83-7.88(m, 1H), 8.16-8.20 (m, 1H).

MS m/z: 332 [M+H]⁺

Melting point: 58° C. (decomposition)IR: 3331, 1533, 1371, 1172, 1156, 908, 855, 655 (cm-1)

(4) Steps 4 to 9

Step 4

(R)—N-[2-(4-hydroxy-butylamino)-1-methylethyl]-2-nitrobenzenesulfonamidemonohydrate (100 g) was dissolved in methanol (570 mL), a solution oftriethylamine (41.5 g) and di-tert-butyl dicarbonate (89.6 g) inmethanol (75 mL) was added dropwise, the mixture was stirred at 15° C.for 1 hour.

After completion of the reaction, the reaction product was concentrated,water was added, and the mixture was extracted with toluene. The organiclayer was washed with 10% saline, and concentrated. The obtained toluenesolution of (R)-tert-butyl 4hydroxybutyl-2-(2-nitrophenylsulfonamide)propylcarbamate (372 g) wassuccessively used for the subsequent reaction.

The NMR spectral data was identical to that in Example 1.

Step 5

A liquid obtained by dissolving triphenylphosphine (179 g) in toluenewas added to the toluene solution of (R)-tert-butyl 4hydroxybutyl-2-(2-nitrophenylsulfonamide)propylcarbamate (372 g). Theliquid was added dropwise to a solution of diisopropyl azodicarboxylate(84.4 g) in toluene (550 mL). After completion of the dropwise addition,the mixture was stirred at 0° C. for 15 hours, and the precipitate wasfiltered. The filtrate was concentrated. The obtained toluene solutionof (R)-tert-butyl3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate (1,235 g)was used for the subsequent reaction.

The NMR spectral data was identical to that in Example 1.

Step 6

Dodecanthiol (83.9 g) was dissolved in N,N-dimethylformamide (800 mL),and lithium hydroxide monohydrate (47.9 g) was added. To this was addeddropwise the toluene solution of (R)-tert-butyl3-methyl-4-(2-nitrophenylsulfonyl)-1,4-diazocane-1-carboxylate (1,235g). After completion of the dropwise addition, the mixture was stirredat 25° C. for 1 hour.

After completion of the reaction, the reaction product was washed withwater. 1 N hydrochloric acid was added to the organic layer, and themixture was extracted with water. Potassium carbonate was added toaqueous layer, the mixture was extracted with toluene, and the organiclayer was concentrated. The obtained toluene solution of (R)-tert-butyl3-methyl-1,4-diazocane-1-carboxylate (195 g) was used for the subsequentreaction.

The NMR spectral data was identical to that in Example 1.

Step 7

Triethylamine (31.7 g), 4-dimethylaminopyridine (0.2 g), toluene (510mL) and N,N-dimethylformamide (350 mL) were added to the toluenesolution of (R)-tert-butyl 3-methyl-1,4-diazocane-1-carboxylate (174 g),and the mixture was cooled to 0° C. 6-chlorosulfonylisoquinolinehydrochloride (41.3 g) was added, and the mixture was stirred at 0° C.for 2 hours.

After completion of the reaction, the reaction product was washed withwater. The obtained toluene solution of (R)-tert-butyl4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate (827g) was used for the subsequent reaction.

The NMR spectral data was identical to that in Example 1.

Step 8

10% sulfuric acid (600 g) was added to the toluene solution of(R)-tert-butyl4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate (825g), and the mixture was stirred at 20° C. for 15 hours.

After completion of the reaction, the liquid was separated, a 10% sodiumhydroxide aqueous solution was added to the aqueous layer, and themixture was extracted with ethyl acetate. The obtained ethyl acetatesolution of (R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline(824 g) was used for the subsequent reaction.

The NMR spectral data was identical to that in Example 1.

Step 9

Methanol (360 mL) was added to the ethyl acetate solution of(R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline (812 g), andthe mixture was cooled to 5° C. To this was added dropwise a solution of35% hydrochloric acid (9.3 g) in methanol (30 mL), and the mixture wasstirred at 2° C. for 20 hours. The precipitated yellowish white solidwas taken by filtration to obtain(R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline hydrochloride(26.7 g).

The NMR spectral data was identical to that in Example 1.

Example 3

(R)-tert-butyl4-(isoquinolin-6-ylsulfonyl)-3-methyl-1,4-diazocane-1-carboxylate (0.100g) was dissolved in ethyl acetate (1.5 mL) and methanol (3.0 mL), and a4 M hydrochloric acid/ethyl acetate solution (0.6 mL) was added at roomtemperature. The mixture was stirred at room temperature for 3 days, andethyl acetate was then added to precipitate a solid. The precipitate waswashed with ethyl acetate and simultaneously filtered to obtain(R)-6-((2-methyl-1,4-diazocan-1-yl)sulfonyl)isoquinoline dihydrochloridein the form of a white solid (0.092 g, yield: 99%).

13;¹H NMR (400 MHz, D₂O, δ ppm): 0.74 (d, J=6.6 Hz, 3H), 1.82-2.18 (m,4H), 3.20-3.39 (m, 4H), 3.48-3.58 (m, 1H), 3.72-3.81 (m, 1H), 4.42-4.56(m, 1H), 8.24 (dd, J=1.8, 8.8 Hz, 1H), 8.34 (d, J=6.2 Hz, 1H), 8.53 (d,J=8.8 Hz, 1H), 8.64 (d, J=6.2 Hz, 1H), 8.75 (s, 1H), 9.61 (s, 1H).ESI-MS m/z: 320 [M+H]⁺, 639 [2M+H]⁺.

1. A 1,4-diazocane compound of formula (8):

wherein R⁴ is an amino protecting group, or a salt thereof.
 2. Thecompound of claim 1, wherein R⁴ is a carbamate-based protecting group,an amide-based protecting group, a phthaloyl group, or ap-toluenesulfonyl group.
 3. A method for producing anisoquinoline-6-sulfonamide derivative of formula (11), optionally as asalt:

the method comprising: reacting a 1,4-diazocane compound of formula (8),optionally as a salt:

wherein R⁴ is an amino protecting group, with an isoquinoline-6-sulfonylhalide of formula (9), optionally as a salt:

wherein X² is a halogen atom; and then carrying out an eliminationreaction of amino protecting group.
 4. A method for producing a1,4-diazocane compound of formula (A), optionally as a salt:

wherein R² is a hydrogen atom or an amino protecting group and R⁴ is anamino protecting group, the method comprising: reacting a compound offormula (6):

wherein R² and R⁴ are independently an amino protecting group, with anazodicarboxylic acid ester and triphenylphosphine.
 5. A method forproducing a compound of formula (B), optionally as a salt or hydrate:

wherein R² is an amino protecting group, R⁴ is a hydrogen atom or anamino protecting group, and Z is a number in a range of from 0 to 1, themethod comprising: reacting a compound of formula (3):

wherein R² is an amino protecting group and R³ is a halogen atom or asubstituted sulfonyloxy group, with 4-amino-1-butanol.
 6. The compoundof claim 1, wherein R⁴ is a carbamate-based protecting group.
 7. Thecompound of claim 1, wherein R⁴ is an amide-based protecting group. 8.The compound of claim 1, wherein R⁴ is a phthaloyl group.
 9. Thecompound of claim 1, wherein R⁴ is a p-toluenesulfonyl group.
 10. Themethod of claim 4, further comprising, after the reacting: eliminatingone of the amino protecting groups.
 11. The method of claim 4, furthercomprising, after the reacting: eliminating both of the amino protectinggroups.
 12. The method of claim 5, further comprising, after thereacting: protecting the amino group.